Immunomodulation of collagen-induced arthritis

Collagen-induced arthritis (CIA) is an experimental autoimmune disease sharing many features with human rheumatoid arthritis (RA). CIA development is dependent on T-cells but anti-collagen type II (anti-CII) antibody production by B-cells is also important. Before the appearance of clinical symptoms there is an increased production of proinflammatory cytokines such as IFN-[gamma] IL-1 and TNF-[alpha] in the draining lymph nodes. This thesis has investigated ways of stimulating or deviating natural pathways of the immune system in order to prevent pathogenic immune responses that are initiated when CIA is induced. One natural immunomodulatory pathway is regulated by the hormone vitamin D3. We demonstrated that an ameliorating effect on CIA could be obtained by treatment using the vitamin D3 analogue MC1288. This treatment did not induce hypercalcemia, a side-effect often associated with this type of treatment. Amelioration was associated with a decrease in anti-CII antibody levels. Induction of type 2 immune responses are often associated with amelioration of arthritis. We used alum, a type 2 inducing adjuvant, which together with collagen II (CII) ameliorated CIA. There was an increased production of IL-4 mRNA in animals pretreated with alum and CII, suggesting that a deviation towards type 2 cytokine production had in fact occurred.

An immune response to foreign antigens may interfere with the pathological immune response to CIL Addition of the foreign antigen OVA to the CII and IFA containing inoculum inhibited disease development of CIA. There was little effect on the humoral response against collagen II. At day 7 IL-4 mRNA was upregulated in the lymph nodes from OVA-inhibited animals compared to diseased controls. The percentage of CD4+[alpha beta]+ lymphocytes having the Ox40 marker was also upregulated in the OVA-inhibited group. In order to use a more effective immunogen than a single protein antigen, a live infection of Trypanosoma brucei brucei (Tbb) was used. When Tbb was infected on the day of CIA induction there was a significant effect on disease development. Similar amounts of Heat killed Tbb could not exert the same effect as live Tbb. The total anti-CII IgG levels were reduced in animals treated with Tbb compared to CIA controls. Analysis of the cytokine mRNA production at days 7 and 28 after immunisation indicated that no shift towards type 2 cytokine production had taken place. In contrast to the previous study using inhibiting OVA, a live Tbb infection is associated with a downregulation of the anti-CII antibody response. In conclusion, these mechanistic studies may give insight into the pathogenesis of rheumatic inflammatory diseases and provide ideas for the development of new therapeutic strategies.

List of scientific papers

I. Mattsson L, Lorentzen JC, Svelander L, Bucht A, Nyman U, Klareskog L, Larsson P (1997). Immunization with alum-collagen II complex suppresses the development of collagen-induced arthritis in rats by deviating the immune response. Scand J Immunol. 46(6):619-624.
https://pubmed.ncbi.nlm.nih.gov/9420626

II. Larsson P, Mattsson L, Klareskog L, Johnsson C (1998). A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia. Clin Exp Immunol. 114(2):277-283.
https://pubmed.ncbi.nlm.nih.gov/9822288

III. Mattsson L, Larsson P, Erlandsson-Harris H, Klareskog L, Harris RA (2000). Parasite-mediated downregulation of collagen-induced arthritis in DA rats. Clin Exp Immunol. 122(3):477-483.
https://pubmed.ncbi.nlm.nih.gov/11122258

IV. Mattsson L, Jansson Å, Mussener E, Erlandsson-Harris H, Klareskog L, Larsson P. Antigen-inhibition of collagen-induced arthritis is associated with up regulation of IL-4 mRNA and induction of 0x40 on T-cells in draining lymph nodes. [Manuscript]